This Program Project has made considerable scientific contributions to dental research in the past, and proposes to continue this tradition in the future. Since the original submission of our first Program Project Grant Application in 1968, we have made effort to promote fundamental research which evolve into science transfer technology for applications in clinical dentistry. This tradition continues. The present application has been designed to investigate the structure, function and molecular genetics of enamel genes and their products, and to transfer this knowledge towards the diagnosis of various types of amelogenesis imperfecta (AI), and the development of enamel bioceramics as a possible dental restorative material. The theme of our competing renewal program project grant is the assertion that enamel is a bioceramic, and that by understanding the structure, function and genetics of normal and abnormal enamel gene products a significant new technology will emerge enabling the fabrication of enamel in vitro. To achieve our goals, three inter- dependent subprojects are proposed to investigate (i) the structural biology of enamel proteins (e.g. amelogenins, tuftelins and enamel proteases), (ii) the function of enamel gene products in tissue-specific biomineralization, and (iii) the molecular genetics of amelogenesis imperfecta. In addition, these studies utilize the methodology of recombinant DNA technology, protein engineering, three-dimensional NMR, X-ray crystallography, computer-assisted molecular modeling, loss of function mutations (e.g., antisense inhibition strategies as well as immunoperturbation studies) using tooth organ culture and cell cultures (e.g. ameloblast cell cultures and transfection studies using odontoblast cell lines), and molecular genetics of human amelogenesis imperfecta including autosomal, X-linked and Y-linked inherited diseases.